Inhibition of PDE2A, but not PDE9A, modulates presynaptic short‐term plasticity measured by paired‐pulse facilitation in the CA1 region of the hippocampus

Abstract

Phosphodiesterase (PDE) inhibitors are currently considered promising therapeutic targets for treatment of cognitive impairment in diseases such as Schizophrenia and Alzheimer's disease. Inhibitors of PDE2A and PDE9A have emerged as potential candidates shown to improve synaptic plasticity and memory function in animals. However, the functional relevance of their putative different localization in the neuron is not understood. Thus, this study aims at elucidating potential presynaptic effects of PDE2A inhibition in comparison to the inhibition of PDE9A. For this purpose, we used paired-pulse facilitation (PPF), a model of short-term synaptic plasticity related to presynaptic function. First, we performed a series of experiments to validate the model in acute rat hippocampal slices using several reference substances including calcium channel blockers, glutamatergic receptor antagonists, and GPCR agonists. Second, we analysed the effect of PDE2A and PDE9A inhibition and their role regulating the influence that the second messengers cAMP and cGMP exert on basal transmission. Our results show that the interplay between the adenylyl cyclase activator forskolin, the soluble guanylyl cyclase activator BAY 41-8543 and the PDE2A inhibitor PF-999 reveals a primarily presynaptic mechanism of action of PDE2A inhibition. On the contrary, inhibition of PDE9A did not alter PPF under similar conditions. In conclusion, these data provide new evidence supporting a role of PDE2A modulating short-term synaptic plasticity. Moreover, this function of PDE2A is suggested to rely on an active modulation of the cAMP hydrolysis as a response to changes in cGMP levels at the presynaptic level.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

“…It is also noteworthy that the present study identified genome-wide significant evidence implicating three phosphodiesterase genes: PDE1C , PDE2A , and PDE4D . In particular, there is growing interest in PDE2A inhibitors as potential agents for cognitive enhancement (Trabanco et al 2016), and evidence suggests that these agents may enhance synaptic plasticity via presynaptic modulation of cAMP hydrolysis (Fernández-Fernández et al 2015). PDE4D inhibition is also under investigatation as a potential therapy for neurodegenerative disease (Ricciarelli et al 2017).…”

Dorsal root ganglion axon bifurcation tolerates increased cyclic GMP levels: the role of phosphodiesterase 2A and scavenger receptor Npr3

“…At more advanced developmental stages, PDE2A expression has a widespread distribution in the central nervous system including the limbic system, olfactory cortex, amygdale, and hippocampus (Van Staveren et al ., ). Our study does not exclude roles of PDE2 in brain functions such as memory formation, inflammatory pain processing, and synaptic plasticity (Hu et al ., ; Kallenborn‐Gerhardt et al ., ; Redrobe et al ., ; Fernandez‐Fernandez et al ., ; Zhang et al ., ).…”

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

“…PDE2A is one of three isoforms of PDE2 and is highly expressed in limbic structures and basal ganglia of the brain and is concentrated in glutamate synapses [127]. Pre-clinical data has shown links to synaptic plasticity and cognition with PDE2A inhibitors having being investigated predominantly as treatments for schizophrenia and migraine, but they are also of interest in degenerative diseases [279][280][281]. 18 F-PF-05270430 is the only PDE2A-specific tracer, thus far, to be translated into man.…”